Environmental contamination with cadmium (Cd) represents a potential health hazard. While this metal is accepted as being extremely toxic in cases of acute exposure, little is known of the potential consequences of chronic exposure to low levels. Cadmium is known to accumulate in several organs of mammals, including the pancreas. Further, decreased pancreatic function has been reported to be a feature of chronic Cd intoxication in humans. The objective of the proposed research will be to extend our preliminary studies on the influence of Cd on carbohydrate metabolism. Earlier results of these laboratories have shown that Cd inhibits insulin secretion from the rat pancreas (in vivo and in vitro). The results of these studies suggest that inhibition of calcium uptake by the pancreatic beta cell may play a part in this inhibition. Isolated pancreatic islets will be employed to assess the effects of Cd on ion fluxes across the pancreatic beta cell membrane. Also, the effects of Cd on beta cell uptake and metabolism of glucose will be studied. A chronic feeding study will be conducted to determine the sensitivity of rat carbohydrate metabolism to dietary Cd. Rats will be fed Cd-containing diets for up to 24 months. Parameters of carbohydrate metabolism, accumulation of Cd in tissues and histopathological changes will be assessed in members of each treatment group at three month intervals. Studies will also be conducted to determine means of preventing and reversing the inhibitory effects of Cd on pancreatic function. Finally, the interactions between Cd and therapeutic agents which are known to influence carbohydrate metabolism will be studied.